Since molecular events underlie clinical events, we hypothesize that unraveling mechanisms of intracellular signaling and metastasis in lung cancers will lead to the identification of targets for therapy for these illnesses and for individul patients. Our roles in the development of EGFR and ALK kinase inhibitors and the discoveries that mutations in EGFR and KRAS genes and ALK re-arrangements underlie sensitivity and resistance to these agents have demonstrated the practicality and potential of this approach. We propose 4 research projects and 3 cores built on an iterative research process uniting clinical and laboratory observations that have linked mutations in tumors to improved outcomes in patients. This grant embraces investigators, technologies, and pathways, each focused by a specific clinical question, proposing to identify targets for therapies in lung cancers. Project 1 ill characterize mediators of metastasis in lung cancers that can serve as targets for intervention. Project 2 attacks pan-refractory KRAS-driven tumors by targeting ERK and its feedback inhibition of upstream signaling in KRAS- and BRAF-driven lung cancers. RP3 will investigate mechanisms and modulators of sensitivity and resistance to EGFR inhibitors, elucidating the role of HER2 and identifying the intrinsic regulatory domains of EGFR-mutant kinases required for function. Project 4 uses innovative mouse models and RNA interference to interrogate lung cancer biology and therapy, focusing on gain of function p53 mutations and oncogenic drivers on 8p that cooperate with EGFR and KRAS mutations. Our Molecular Profiling & Pathology Core crystallizes nearly a decade of experience in specimen collection, precise pathologic characterization in mouse and annotated human samples, mutation testing, and gene profiling in lung cancers to enrich and support each project. The Biostatistics and Bioinformatics Core ensures consistency in biostatistical analyses, unifies information exchange, and provides projects with additional analytic capabilities. The Administration Core facilitates communication and dissemination of findings and provides the forum for the PIs and the Executive and Scientific Advisory Committees to ensure rigorous scientific review and reassessment of priorities.